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Advances in Cancer Care CLINICALONCOLOGY.COM • JULY 2009

POLICY & MANAGEMENT

Hospitals slow in adopting e-health records. SUPPORTIVE CARE

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High risk for parainfluenza virus infection identified in leukemia and HSCT patients. PEOPLE AND PLACES

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Kao accused of medical errors. Vogelstein, Bloomfield, Olopade win awards. SOLID TUMORS

Study reveals limitations of gemcitabine-cisplatin regimens in bladder cancer. Clinicians not adequately informing patients about breast cancer treatment options. Sorafenib dosing poses problem for Asian patients.

Standard of Care Established For Inoperable Biliary Cancer

Immunotherapy Increases Cure Rate In Neuroblastoma Orlando, Fla.—Adding an antibodybased immunotherapy to the standard therapy of retinoic acid (RA) improved overall survival by 10% and event-free survival (EFS) by 20% at two years in patients with high-risk neuroblastoma, according to a recent study. Results from this Phase III trial were reported at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 10067z). According to Alice Yu, MD, PhD, professor of pediatric hematology/oncology at the University of California, San Diego (UCSD) and the UCSD Moores Cancer Center, past trials have shown that most patients who are diseasefree after two years are cured. “It is very exciting to have a new treatment option for this disease, and we hope to see IMMUNOTHERAPY, page 9

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CLINICAL TRIALS

A list of Phase II and III trials initiated within the past 30 days. Selective publication of drug data suggests bias. S PEC I AL O FF ERS

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Will Second-Gen TKIs Move to First-Line Therapy for CML? San Francisco—Several studies are providing evidence that second-generation tyrosine kinase inhibitors (TKIs) may provide more rapid control of chronic myelogenous leukemia (CML) than imatinib (Gleevec, Novartis), when used as first-line therapy. One study was conducted with dasatinib (Sprycel, Bristol-Myers Squibb) and the other two with nilotinib (Tasigna, Novartis). The three studies were not randomized controlled trials, but each used previously reported data on imatinib to show the newer agents were associated with substantially faster times to complete cytogenetic response (CCyR). see TKIs, page 6

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Histopathology of gallbladder adenocarcinoma incidentally found in a cholecystectomy specimen.

linicians have the first standard of care for patients with metastatic or locally advanced biliary cancer. The combination of gemcitabine (Gemzar, Eli Lilly) and cisplatin improved overall survival by more than three months compared with treatment with gemcitabine alone, according

to results from a Phase III trial. The news was reported at the annual meeting of the American Society of Clinical Oncology (abstract 4503). “Combination chemotherapy with cisplatin and gemcitabine significantly improves see STANDARD OF CARE, page 8

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POLICY & MANAGEMENT

Study Says Off-Label Resources Are Outdated, Flawed

n 2008, the Centers for Medicare & Medicaid Services (CMS) added three new compendia that clinicians can cite when seeking payment for off-label cancer treatments. The move was initially well met because the two existing compendia were either in flux or becoming out of date, potentially limiting patient access to affordable cancer care. But a recent study in the Annals of Internal Medicine (2009;150:336-343, PMID: 19221366) suggests that all is not well with the expanded compendia canon. Using

14 common off-label cancer treatments as a basis for comparison, the researchers found that all but one of the compendia cited literature from 2001 or earlier to support the indications. Many other problems were found, including “scanty and inconsistent” evidence for the off-label uses, as well as a lack of transparency that made it difficult to rule out “potential biases or conflicts of interest” that could have influenced content. These shortcomings led the authors to see OFF-LABEL, page 3

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NEW PRODUCT Dako launches new ArtisanLink Special Stains System. See page 6.

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Reimbursement

OFF-LABEL continued from page 1 �

raise the following question: “In their current state, can we rely on the compendia as authoritative, comprehensive and timely sources of information on offlabel indications in oncology?” Amy P. Abernethy, MD, the lead author of the Annals study and a cancer researcher at Duke University Medical Center, in Durham, N.C., acknowledged that the bulk of her analysis was done in 2006—two years before the new compendia were accepted. “But we did include current editions of those titles at the time of our study, and the flawed updating methods we found raise questions about the timeliness of the texts that may still persist.” Philip E. Johnson, MS, RPh, FASHP, pharmacy director at H. Lee Moffitt Cancer Center in Tampa, Fla., said such a conclusion is too far-reaching. In fact, Mr. Johnson applauded one of the newly added references, the National Comprehensive Cancer Network’s NCCN Drugs and Biologics Compendium, for accomplishing exactly what the Annals authors said they failed to find—consistent, timely updates to its listings. “I only had to look at the NCCN compendia’s current Practice Guidelines in Oncology (v.2.2009) to validate the timeliness of this document,” he said. “Three papers from 2008 were included, detailing the role that K-ras mutations play in patient response to EGFR [epidermal growth factor receptor] inhibitors for colorectal and other cancers.” All three studies, he said, provide new, “category 2A guidance” for the use of these agents.1-3 Dr. Abernethy said she was “heartened” to see that the NCCN compendium contained the EGFR updates. “But the fact remains that when we did our research in 2006, and repeated the analysis in 2008 for one of the indications, many of the citations in the compendia were outdated.” This suggests, she said, that users of the compendia “cannot trust that updating has indeed happened.” Mr. Johnson said the existence of old, “even ancient references” should not be construed as evidence that a compendium is outdated or flawed “if the

‘These references give us a better chance than we had previously to document the legitimacy of many off-label cancer therapies, and in the process, to get paid for the often lifesaving medications we’re giving our patients.’ —Philip E. Johnson, MS, RPh, FASHP

references support historical usage.” But he acknowledged that timeliness is “the far more important factor” in assessing the compendia’s utility. In the case of the NCCN compendium, he stressed, timeliness is the strength of the text. “When a practice-changing treatment protocol is presented at ASCO, for example, NCCN can build that protocol into its therapeutic guidelines, often within eight to 10 weeks, and then add it to their compendia,” Mr. Johnson said. “Clinicians can then use the new listing to at least make their case for reimbursement.” Dr. Abernethy said that such timeliness “may be evident in some areas. But it was not, unfortunately, evident in the areas we reviewed.”

Getting Paid The publication of the Annals study is not the only flashpoint in the debate over CMS’s compendia-based approach to reimbursement for offlabel cancer care. The agency’s decision to let local insurers, known as fiscal intermediaries (FIs), make regional coverage determinations on behalf of the federal agency has also triggered concern. Christian Downs, MHA, JD, deputy

executive director of the Association of Community Cancer Centers (ACCC) in Rockville, Md., said that such a localized payment policy can lead to a patchwork pattern of coverage that has frustrated some oncologists. “If you leave these decisions up to FIs, yes, they can conduct a detailed analysis and make good decisions,” Mr. Downs said. “But you also end up with a checkerboard approval process, where something is approved in Nevada but not in Missouri. A more consistent payment policy would certainly benefit everyone.” That type of direction could come from CMS. But the agency has said that the listing of an off-label use in a compendium does not guarantee coverage; those determinations must be made by local FIs. Mr. Johnson said he understands the rationale behind the current CMS payment policy. “I realize that [having FIs determine coverage] can cause some confusion across regions, but there are too many individual patient variables that have to be considered for any blanket coverage policy to be workable,” he said. “You just cannot have the compendia be the final authority on whether a given off-label use is covered.” He added, however, that this approach “does require that practitioners work more closely with their state FIs to expand therapy indications, which can be time-consuming.”

Gang of Four Although the expanded lineup of compendia is new, the policy that brought them into existence is not: In 1993, the federal government issued a statute that requires accepted compendia to be used as resources in determining the insurability of anticancer drugs and biologics for off-label use. But because of attrition and the vagaries of publishing, for several years the cancer community only had two functioning compendia—the American Hospital Formulary Services Drug Information (AHFS DI), which is published by the American Society of Health-System Pharmacists (ASHP), and a text put out by the United States Pharmacopeia (USP). “In 2007, when the USP compendia was purchased and rolled into another publication, we faced the possibility of being left with only one compendia,” Mr. Downs said. “That was

not an ideal situation. Too many coverage determinations would be based on too little data, and payment decisions could have been flawed.” That’s why CMS stepped in and announced in 2008 that a total of four compendia would be considered as the basis for deciding on payment for offlabel drug reimbursement—the ASHP’s AHFS DI, plus three new titles: the NCCN Drugs & Biologics Compendium, Thomson Micromedex’s DRUGDEX, and Clinical Pharmacology, a drug information and medication management reference from Gold Standard, an Elsevier company. Peter Ashkenaz, deputy director of media relations at CMS, said that if any of the four compendia determine that there is enough data to support a “medically acceptable use for a drug or biologic,” it can be covered by CMS. However, if one of the compendia issues a “not recommended” status for an off-label use, “that overrules any positive recommendation.”

The Annals Study The comparative nature of that policy is what worries the Annals authors. For comparisons to be valid, they pointed out, the compendia should share a common method of evaluating off-label cancer therapies. But according to the researchers, that is not the case, based on their analysis of the CMS-approved compendia as well as two unapproved texts. For their analysis, the researchers gathered information on each compendium’s methods from a variety of sources, including published information and details obtained from senior editors during telephone interviews and surveys. They found several inconsistencies in how evidence for off-label treatments are assessed, updated and described: • Not all compendia included revision dates for off-label monographs, and when provided, they did not clearly indicate which content was revised. • Not all compendia explicitly linked recommendations to supporting evidence via specific citations. • Aspects of treatment protocols varied significantly, such as stage of cancer during which the agent should be prescribed; whether treatments should be considered first- or second-line therapy; whether monotherapy or combination therapy is indicated; and the type of drug comparators used in clinical trials. As for the lack of timeliness that the authors cited, that was best illustrated by their analysis of the offlabel use of gemcitabine (Gemzar, Lilly) for bladder cancer. In 2006, their review of the literature identified 43 published Phase I to III studies and 15 conference abstracts that could potentially support a bladder cancer indication. Yet only up to seven of those see OFF-LABEL, page 4 �

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CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Reimbursement

OFF-LABEL continued from page 3 �

citations were included in the compendia. By 2007, an additional 25 reports on gemcitabine were published. Yet only one compendium, DRUGDEX, showed signs that they were doing at least some tracking of the literature—they increased their citations from three to 11. The other compendia, in contrast, “had little or no change,” the authors reported. Moreover, none of the compendia included a follow-up study on the original Phase III gemcitabine bladder cancer trial. The findings on gemcitabine provided “a case-in-point demonstration that the compendia did not follow their stated policies with regard to update cycles,” the authors reported. In a letter to the Annals editor, the ASHP took issue with the investigators’ use of gemcitabine as a point of criticism. Citing the newer references “does not change the determination of medical acceptance, which was established by the original [gemcitabine] citation,” the letter stated. “Rather than cataloguing all applicable published references, determining medical acceptance is the statutory charge for compendia.” The more appropriate time to add a

new reference, the letter noted, would be “when new evidence substantially changes medical acceptance (e.g., survival benefits, toxicity).” Dr. Abernethy questioned how users of the compendia could be confident that such new evidence is being added consistently, given the flaws found in the citation

compendia without a clear rationale for the exclusion was yet another source of concern for the Annals authors. The lack of transparency on this issue “raises the possibility of bias or conflict of interest,” the investigators wrote. In fact, a detailed review of conflicts of interest in compendia “is forthcoming,” Dr. Abernethy said.

‘With more than 50% of patients receiving off-label anticancer treatments, to eliminate or reduce the number of compendia [because of potential bias] could create major access issues.’ —Ernest R. Anderson Jr., RPh process. Indeed, “it is impossible to know if you are accessing the most up-to-date information,” she said.

Lack of Transparency The fact that certain off-label cancer indications were excluded in some of the

Ernest R. Anderson Jr., RPh, president of the ACCC, acknowledged that “there is an inherent potential for conflicts of interest in the [compendia] process.” But he stressed that “all compendia make sincere efforts to limit those conflicts.” Mr. Anderson added that the individuals who

review material for inclusion in the compendia “are experts in the field of oncology, and as a result of our … drug development [system], they almost always have some kind of ties to [the pharmaceutical industry]. With more than 50% of patients receiving off-label anticancer treatments, to eliminate or reduce the number of compendia [because of potential bias] could create major access issues.” For Mr. Johnson, having an expanded number of compendia “is a definite positive,” despite the Annals study, he said. “These references give us a better chance than we had previously to document the legitimacy of many off-label cancer therapies, and in the process, to get paid for the often lifesaving medications we’re giving our patients.” —David Bronstein

References 1. Lievre A et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 2. Amado IG et al. Wild-type KRAS is required for panitunumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26:1626-1634. 3. Etienne-Gimeldi MC et al. KRAS mutations in treatment outcome in colorectal cancer in patients receiving exclusive fluoropyrimidine. Clin Cancer Res. 2008;14:4830-4835.

Electronic Records

e-Health Records Still Lagging Most policymakers agree that widespread adoption of health information technology can improve patient care. Yet only a small percentage of hospitals have implemented even a basic version of one highly touted technology—the electronic health record (EHR), according to a survey of acute care facilities. The survey team, led by Ashish K. Jha, MD, MPH, from Harvard School of Public Health, in Boston, used two definitions of EHR systems to assess adoption rates—”comprehensive” and “basic.” Comprehensive systems were defined as those that were operational in all clinical units and included multiple components, such as clinical documentation, diagnostic tests and computerized provider order entry (CPOE). Two types of basic systems were tracked—those with physicians’ notes and nursing assessments and those without these features. The researchers found that 1.5% of the surveyed hospitals had a comprehensive EHR system in place (95% confidence interval [CI], 1.1%-2.0%). Results were slightly better for basic systems: 7.6% of the respondents had implemented such a system, with physicians’ notes and

nursing assessments employed in at least one clinical unit (95% CI, 6.8%-8.1%). Basic EHR systems without those features were in place at 10.9% of responding hospitals (95% CI, 9.7%-12.0%). Nearly 3,000 responding hospitals were included in the analysis, the researchers reported in the New England Journal of Medicine (2009;360:1628-1638, PMID: 19321858). Hospitals were more likely to have implemented an EHR system if they were larger, were a major teaching hospital, were part of a multisite health network, were located in an urban area and had a dedicated coronary care unit. Geographic location and profitability did not influence the likelihood of having an EHR system. As far as barriers to adding EHRs, financial constraints were most often cited. Other challenges included physician

resistance and concerns about a lack of a standardized approach for exchanging information among hospitals and physician offices. Dr. Jha and his colleagues stressed that the results were not all dire. Although “90% of U.S. hospitals in the survey do not even meet the requirement for a basic [EHR],” they wrote, “many functionalities that underlie electronic records systems have been widely implemented.” For example, they reported that for “a sizeable portion” of respondents, laboratory and radiology reports,

medication lists and certain decisionsupport functions were available electronically at their institutions or were in the planning stages. To facilitate more widespread adoption of EHR systems, the authors recommended “rewarding hospitals—especially financially vulnerable ones—for using health information technology [IT].” They added that incentives also should be created for increasing IT staff and harmonizing IT standards. —Sarah Tilyou

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Parainfluenza Virus

In Leukemia and HSCT Patients …

High Risk for Parainfluenza Virus Infection Identified Washington—Patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT) appear to be at high risk for infection with parainfluenza virus (PIV), which is associated with high mortality rates, according to a new study. In addition to this bad news, the same study revealed that treatment with aerosolized ribavirin is ineffective. The study was presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the 46th Annual Meeting of the Infectious Diseases Society of America (presentation V-4144). “Parainfluenza virus is an important cause of community-acquired respiratory virus. It has been recognized as a possible cause of serious infections in immunocompromised patients. Those undergoing hematopoietic stem cell transplantation or therapy for hematologic malignancies are at increased risk,” said study investigator Santosh Hanmod, MD. “Currently, there is no licensed prophylaxis or antiviral therapy for severe PIV infections.” Dr. Hanmod is a pediatric resident at Wayne State University School of Medicine, Detroit.

Retrospective Study While Dr. Hanmod was at M.D. Anderson Cancer Center in Houston, he conducted a retrospective study of 200 patients infected with PIV in an attempt to characterize the problem. Dr. Hanmod’s mentor during this project was Roy Chemaly, MD, MPH, associate professor of medicine and director of infection control at M.D. Anderson. The study included 80 patients with leukemia (40%) who did not undergo HSCT and 120 patients with a variety of cancers who did undergo HSCT (60%). The latter group included patients who had acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, myelodysplastic syndrome, nonHodgkin’s lymphoma, Hodgkin’s lymphoma, multiple myeloma, ovarian cancer and breast cancer. The mean age of the patients was 52 years (range, 17-84 years), 153 (77%) of them were white, and 130 (65%) had a relapsed/refractory malignancy and/or were currently receiving chemotherapy. Of the HSCT recipients, 97 (81%)

had an allogeneic HSCT, and the median number of days from diagnosis to HSCT was 70. Further review of the patients’ records revealed that 70% had an upper respiratory infection (URI) and 30% had pneumonia. More of the patients with leukemia who did not receive HSCT progressed from URI to pneumonia compared with patients who received HSCT (40% vs. 17%; P=0.002). The patients with leukemia who did not undergo HSCT also had higher APACHE (Acute Physiology and Chronic Health Evaluation) II scores (14 vs. 10; P<0.001). Overall, the researchers found that symptoms resolved completely in 88% of the patients. A multiple logistic regression model showed that symptoms were more likely to resolve completely in patients with an APACHE II score below 15 and in patients who did not require mechanical ventilation. Altogether, 12% of the patients died with active PIV infection at 30 days of follow-up. Dr. Hanmod said that no statistically significant difference was noted between the mortality rate in patients who received HSCT and the mortality rate in those who did not (10% vs. 6%; P=0.5). Aerosolized ribavirin, which was given to 19 patients (10%), did not offer any benefit in terms of duration of symptoms, length of hospitalization or progression to pneumonia or mortality. The rest of the patients were given supportive care without any antiviral medications. “We found that aerosolized ribavirin was not effective either in reducing the duration of symptoms of PIV infection or prevention of progress from URI to pneumonia in our patient population,” said Dr. Hanmod. “However, ours is a retrospective study, and aerosolized ribavirin was used in a relatively small number of patients. There could be an element of selection bias. Those patients who are more sick at presentation may have been subjected to the treatment with aerosolized ribavirin.” The most common cause of death among the patients studied was acute respiratory failure and/or multiple-organ failure. Until now, reports on the characteristics of cancer patients and the morbidity and mortality associated with PIV infection have been rather limited. In addition, the results in published reports on the efficacy of ribavirin in patients with PIV pneumonia have been mixed.

Take-Home Message “Pneumonia due to communityacquired respiratory viruses (including PIV) and deaths resulting from them have been a great concern in the

Transmission electron micrograph of parainfluenza virus. Two intact particles and free filamentous nucleocapsid.

‘The important take-home message for the oncologist managing leukemia patients is that PIV could be a significant cause of mortality and morbidity in these patients, and since we don’t have a definitive drug/vaccine prophylaxis or an effective treatment modality as of now, infection control remains the single most [important] strategy in preventing PIV infection in this patient group.’ —Santosh Hanmod, MD

management of patients with leukemia and those undergoing HSCT,” said Dr. Hanmod. “The important take-home message for the oncologist managing leukemia patients is that PIV could be a significant cause of mortality and morbidity in these patients, and since we don’t have a definitive drug/vaccine prophylaxis or an effective treatment modality as of now, infection control remains the single most [important] strategy in preventing PIV infection in this patient group.” Paul Petruska, MD, director of the division of hematology/oncology at Saint Louis University School of Medicine, St. Louis, said PIV infection in patients with cancer is an area that needs further investigation, especially because of the high mortality rates. He was surprised by the high incidence of PIV infections. “I have not seen this infection in our patients, and the numbers from this study sound very high. So yes, it is surprising news. It was interesting that the investigators found that medical therapy did not influence outcomes,” said Dr. Petruska. “I think oncologists may want to talk to their infectious disease specialists about this and what treatment should be given since the treatment used in this study didn’t work.”

Ken Haller, MD, associate professor of pediatrics at Saint Louis University School of Medicine, also said the study was important. “I think it’s very significant. While patients who are undergoing stem cell transplantation are strictly isolated in the period immediately after the procedure, it seems that the parainfluenza virus infections that caused problems were encountered some time after patients had left the unit,” said Dr. Haller. “This is troubling because one would assume that these patients would have pretty much a fully functional immune system by the time they encountered these viruses.” He also said it is an area that needs further study. “While this study showed an association between PIV and poor outcomes in these patients, a better understanding of why this happens remains to be found,” Dr. Haller said. “In the meantime, it’s an excellent reminder to do those commonsense things to prevent viral infection that we hear about over and over again at this time of year—wash your hands, drink lots of fluids, get plenty of rest and avoid sick people if you are at increased risk for a bad outcome.” —John Schieszer

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Chronic Myelogenous Leukemia 100

TKIs continued from page 1 �

High Rates of CCyR “Dasatinib can induce a very high rate of complete cytogenetic responses, and these responses occur very early,” said Jorge Cortes, MD, University of Texas M.D. Anderson Cancer Center, in Houston. Dr. Cortes is the senior author on two such ongoing studies, one of dasatinib and the other of nilotinib that were presented at the most recent annual meeting of the American Society of Hematology (ASH). Early results suggest fairly dramatic advantages to the newer TKIs. In the dasatinib study, the CCyR rate was 90% at six months (ASH abstract 182). In the nilotinib study, the CCyR was 100% at six months (ASH abstract 446). In comparison, historical CCyR rates in patients receiving imatinib at Dr. Cortes’s institution were 48% and 82% for the 400 mg and 800 mg doses, respectively, at six months. In IRIS (International Randomized study of Interferon versus ST1571), the CCyR in patients receiving imatinib was less than 30% at six months (N Engl J Med 2006;355:2408-2417, PMID: 17151364). Similar evidence is being provided from a multicenter European trial of nilotinib, also reported at the most recent ASH meeting. In that study, led by Gianantonio Rosti, MD, Institute of Hematology Seragnoli, in Bologna, Italy, the CCyR rate at six months was 97% (ASH abstract 181). Although all three studies are relatively small with insufficient follow-up to confirm that the CCyR rates are sustained, there is no reason to believe that a comparable duration of response will not be seen. In fact, results from these new trials are particularly exciting because data from previous TKI studies have suggested that early response is a predictor of sustained response, indicating that long-term outcomes may be even better for the newer agents.

Study Details In the dasatinib study, 52 patients with previously untreated CML were randomized to receive this newer TKI in a dose of 100 mg once daily or 50 mg twice daily. The median age was 45 years, but patients as old as 82 were enrolled. The majority of the patients were rated as low risk on the Sokal scale. The primary objective was to evaluate the major molecular response (MMR) at 12 months. In the 48 evaluable patients, CCyR climbed from 78% at three months to 90% at six months and 95% at 12 months. The MMR reached 35% at 12 months, climbed to 48% at 18 months and further increased to 64% at 24 months. The event-free survival (EFS) at 24 months was 84%, but Dr. Cortes noted that two patients lost response due to noncompliance with

CCyR Rate at 6 Months, %

100

Imatinib

Nilotinib

Dasatinib

90 82

60 48 40

<30

Dasatinib, Cortes Study

Nilotinib, Cortes Study

Nilotinib, Rosti Study

400 mg Imatinib, IRIS

400 mg 800 mg Imatinib, Imatinib, M.D. Anderson M.D. Anderson Data Data

Figure. Comparison of CCyR rates at six months in patients with CML. treatment. When these two patients are eliminated from the analysis, the EFS at 24 months reaches 89%. The rate or types of adverse events with dasatinib do not appear to differ substantially from those associated with imatinib. The most common grade 3 nonhematologic adverse events were pruritus or other skin reactions (13%), fatigue (6%) and peripheral neuropathy (4%). The grade 3 or 4 hematologic adverse events included neutropenia in 21%, thrombocytopenia in 12% and anemia in 9%. Almost 40% of the patients were given a dose reduction, mostly because of elevated liver enzymes. Slightly more than half had at least one dose interruption, but few patients discontinued therapy. Although the 100 mg once-daily and 50 mg twicedaily doses did not differ significantly on safety or efficacy, there were trends for an advantage for the oncedaily dose for both. As a result, Dr. Cortes expected further studies to be limited to the once-daily dose. In the M.D. Anderson study of nilotinib, 49 patients with previously untreated Philadelphia chromosome– positive (Ph+) CML have been treated with 400 mg twice daily of this TKI. Median follow-up so far is 13 months. In addition to the 100% CCyR at six months, the MMR reached 45% at six months and 52% at 12 months. There have been two cases of a confirmed complete molecular response. Side effects were consistent with those previously reported. Two patients discontinued treatment because of toxicity; one had a pericardial effusion and the other had persistent liver dysfunction. In the European nilotinib study, 73 patients with previously untreated CML were enrolled at 18 centers of the GIMEMA CML Working Party in Italy. The median age was 51, with a range of 18 to 76 years. All received 400 mg nilotinib twice daily. Although Dr. Rosti cautioned that the study data were not yet

mature, the early activity of the drug has also been impressive. In addition to the 97% CCyR rate at six months, the MMR rate was 66%. Again, the type and rate of adverse events was consistent with previous studies of TKIs. Although 47% of patients had at least one treatment interruption, the median average dose in follow-up so far has been very close to the intended dose. Grade 3 or 4 adverse events, including both nonhematologic and hematologic toxicities, were “manageable with appropriate dose adaptations,” said Dr. Rosti. He also noted that there was a substantial decrease in adverse event rates in the second six months compared with the first six months in nonhematologic grade 2 or 3 adverse events.

Not Unexpected Currently, nilotinib and dasatinib are reserved for patients with a primary resistance to imatinib, but the results of the three studies were not wholly unexpected. Interest in evaluating these agents for firstline therapy has been produced by the often impressive responses achieved in imatinib failures as well as from experimental studies. For example, nilotinib “has a higher binding affinity and selectivity for Abl with respect to imatinib, being 20 to 50 times more active in imatinib-sensitive cell lines and is highly effective in imatinib-resistant patients across every disease phase,” Dr. Rosti said. The high response rates of dasatinib are also consistent with its selectivity for Abl relative to imatinib. The obvious question is whether these newer agents should replace imatinib, but Dr. Cortes urged caution. “I think these results are important, but they are not enough to draw conclusions [about the role of these agents as first-line therapy]. We really need head-tohead data,” he said. —Ted Bosworth

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PEOPLE AND PLACES

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Around the Water Cooler This new section will bring you news about people and places in the field of oncology. If you have news to share (new job, award, cancer center closure or expansion, etc.), please send information to korourke@mcmahonmed.com.

ccording to an article in The New York Times, Gary D. Kao, MD, PhD, has been accused of mishandling scores of radioactive seed implants at a Philadelphia Veterans Affairs hospital run by the University of Pennsylvania. According to reporting by The New York Times, he was responsible for 92 of 116 substandard cancer treatments over a span of more than six years. In these procedures, seeds did not end up where they should have and, in some cases, the seeds ended up in other organs. Allegedly, the radiation safety committee at the VA hospital was aware of the problem but failed to take action. At a recent Congressional panel hearing on the matter, Dr. Kao did not deny placing large numbers of seeds outside the patients’ prostate, but said that investigators were wrong to single him out. He said that what he is being accused of is a recognized “risk of the procedure. According to The New York Times, Steven A. Reynolds, who oversees materials safety at the Nuclear Regulatory Commission, which regulates all nuclear materials, disputes Dr. Kao’s assertion. Mr. Reynolds said that cases where large numbers of seeds miss the prostate, “happen very, very infrequently.”

Vogelstein Receives Award

ert Vogelstein, MD, director of the Johns Hopkins Kimmel Cancer Center, Baltimore, received this year’s American Society of Clinical Oncology “Science of Oncology” Award at the group’s annual meeting in Orlando, Fla.

Dr. Vogelstein was selected in recognition of his decades of research, uncovering the specific genes and mutations responsible for colorectal cancer and for establishing a genetic model for how all cancers form and progress. He discovered the APC gene, which controls cell growth in the colon, and has made significant contributions to understanding the role of the p53 gene in the development of cancer. Dr. Vogelstein and his team are using their findings to develop tests that identify individuals at risk for developing colon cancer, to track treatment progress and to search for new therapies. His lab also developed sensitive blood tests that currently are being used to identify patients with inherited mutations in genes linked to colorectal cancer. In the past year, Dr. Vogelstein and colleagues mapped the complete genetic blueprint for pancreatic and brain cancers; they completed the genome maps for breast and colorectal cancers in 2007. Dr. Vogelstein also is the Clayton Professor of Oncology, a Howard Hughes Investigator and director of the Ludwig Center for Cancer Genetics and Therapeutics at the Johns Hopkins Kimmel Cancer Center.

Bloomfield Wins Karnofsky Award Clara D. Bloomfield, MD, a professor at The Ohio State University Comprehensive Cancer Center, in Columbus,

received the 2009 David A. Karnofsky Memorial Award at the recent annual meeting of the American Society of Clinical Oncology. Dr. Bloomfield is a pioneering researcher in the field of adult leukemia and lymphoma. Dr. Bloomfield’s work has enriched the understanding of the mechanisms and characteristics of leukemia and lymphoma and contributed to establishing a new internationally accepted classification system for these disorders. Her work has been used to help create clinical practice guidelines and has been at the forefront of strides being made in the use of personalized medicine for patients with leukemia and lymphoma. Dr. Bloomfield was the first to use the immunophenotypic, cytogenetic and molecular genetic features of neoplastic cells in leukemia and lymphoma to identify appropriate treatments for patients. She and her colleagues discovered the Philadelphia chromosome in acute lymphoblastic leukemia in 1975. This changed the standard of care for this disease to stem cell transplantation when feasible. Dr. Bloomfield also first reported the biologic and genetic markers important in the diagnosis of acute myelogenous leukemia (AML) and that the effectiveness of the dose of a drug depended on cytogenetics in this disease. In 2001, the World Health Organization LBJ Photography

Kao Accused of Serious Medical Errors

mandated the use of cytogenetics for diagnosis in AML. The National Comprehensive Cancer Network followed suit in 2005. Dr. Bloomfield currently is researching molecular changes in AML and identifying genes involved in the disease. Recently, she and her colleagues showed for the first time that a single microRNA has independent prognostic significance in AML.

Olopade Honored

lufunmilayo Olopade, MD, has received the American Society of Clinical Oncology–American Cancer Society Award for pioneering research in breast cancer genetics. This award honors an individual who has made significant contributions to the prevention and management of cancer. Some of Dr. Olopade’s research has focused on developing better tools and methods to manage triple-negative breast cancer, which is overrepresented in young black women and women with BRCA2 mutations. Dr. Olopade is the Walter L. Palmer Distinguished Service Professor in Medicine and Human Genetics, associate dean for Global Health and director of the Center for Clinical Cancer Genetics at the University of Chicago. An oncologist for more than 25 years, she has devoted her career to shifting the focus away from the treatment of cancer to the overall prevention of it. As an internationally recognized hematologist/oncologist, she specializes in cancer risk assessment, prevention, early detection and treatment of aggressive breast cancer that disproportionately affects young women. PRN Information Resources

Medpedia: New Web Resource Will Mimic Wikipedia M Medpedia is currently edpedia Project is creating a comprehensive online medical encyclopedia. The project—to mimic Wikipedia—will offer the largest communal collection of medical information covering the body, drugs and overall health. This collective will include participation from physicians, medical schools, hospitals and health organizations. Taking a page from the communal spirit of the Wikipedia Web site, Medpedia will house information free of copyright restrictions for noncommercial use through the GNU Free

Documentation License. Faculty members from various institutions will contribute information, creating a continuous stream of up-todate content available at the click of a mouse. The Medpedia Project hopes to create a community of editors that can link Web pages for information on over 30,000 diseases, more than 10,000 prescription drugs and thousands of medical procedures. “It’s feeling inevitable that all the medical and health information will be available worldwide at no charge via an open, collaborative

requesting applications from MDs and PhDs to serve as main content editors. platform like Medpedia,” said Linda Hawes Clever, MD, MACP, a clinical professor at the University of California, San Francisco School of Medicine. Medpedia pages will house data

catering to the common patient—presented in layman’s terms—in addition to more technical pages for medical practitioners. The site will also include photographs, videos, sound bytes and images pertaining to various disease conditions. Medpedia is a long-term project, just getting started. The site is up and running and is currently requesting applications from MDs and PhDs to serve as main content editors. Visit www.medpedia.com to learn more. —Seth Kandel

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Biliary Cancer Gemcitabine + Cisplatin

STANDARD OF CARE continued from page 1 �

overall survival,” said Juan Valle, MD, a medical oncologist at the University of Manchester in the United Kingdom. “Median survival was improved from 8.3 months to 11.7 months. The risk of death was reduced by 30%. This is the first demonstration of survival benefit in advanced biliary tract cancer. The benefit appears to be gained with no significant added toxicity.” Biliary tract cancers in the study were defined as cholangiocarcinomas, gallbladder cancer and ampullary cancer. Cholangiocarcinoma accounts for 3% of all gastrointestinal cancers globally. Surgery offers the only chance for a long-term cure, but most cases are inoperable. Five-year survival is estimated to be between 5% and 10%. Until now, clinicians have not had a standard of care for patients with advanced biliary cancer, because Phase III trials have been underpowered and uncommon. This is due in part to a lack of multicenter collaboration, which is needed for clinical trials involving a rare cancer. Conducting clinical trials has also been difficult because the disease mostly occurs in the elderly and is histologically and cytologically difficult to confirm. At the 2006 ASCO-Gastrointestinal Cancers Symposium (abstract 98), researchers reported that in a study of 86 patients (ABC-01 trial), adding cisplatin to gemcitabine improved median time to progression (TTP)

and six-month progression-free survival (PFS; 4.0 vs. 8.0 months and 47.7% vs. 57.1%, respectively). Because of that success, this study was extended and a Phase III trial (ABC-02) recruited additional patients. All patients were recruited from 34 centers in the United Kingdom. Patients were randomized to receive either cisplatin (25 mg/m2) followed by gemcitabine (1,000 mg/m2 days 1 and 8 every 21 days) for eight cycles, or gemcitabine alone (1,000 mg/m2 on days 1, 8 and 15 every 28 days) for six cycles, stratified by extent of disease, site of primary tumor, ECOG score and center. At the recent ASCO meeting, investigators reported the results from a pre-planned combined analysis of the ABC-01 and ABC-02 trials of 410 patients. Median PFS was improved from 6.5 to 8.4 months with the combined treatment (P=0.003). With a median followup of 6.1 months and 263 deaths, median overall survival was greater with the combination of gemcitabine and cisplatin than with gemcitabine alone (11.7 vs. 8.3 months; P=0.002; hazard ratio, 0.70; 95% confidence interval, 0.56-0.88). Toxicity was similar between the two arms. “We would like to recommend cisplatin and gemcitabine as a worldwide standard of care and the backbone for further studies,” Dr. Valle said. Other clinicians not involved in the study agreed. “[This study] is a well-designed, well-conducted study, with an outstanding recruitment,” said Christophe Louvet, MD, PhD, a professor in the Department

Overall Survival, mo

Gemcitabine

11.7

8.3

8 6 4 2 0

Figure. Comparison of median overall survival. of Medical Oncology at Pierre & Marie Curie University Paris VI, at the Hospital Saint-Antoine in Paris. “This study results in a new standard of care.” The median age of the patients in the study was 63 years; 48% were male; 77% had metastatic disease; 23% had locally advanced disease; 37% had cancer of the gallbladder; 58% had cancer of the bile duct; and 5% had cancer of the ampulla. The study was conducted under the auspices of the National Cancer Research Institute and funded by Cancer Research UK, with the help of an unrestricted educational grant from Lilly Oncology. It was sponsored by the University College of London, which coordinated it through their clinical trials unit. —Kate O’Rourke

Bladder Cancer

In Muscle Invasive Bladder Cancer ...

Researchers Compare MVAC To Gemcitabine-Cisplatin Orlando, Fla.—Neoadjuvant chemotherapy with gemcitabine-cisplatin (GC) provides little benefit in patients with muscle-invasive bladder cancer who undergo open radical cystectomy. This conclusion comes from a small study at Cleveland Clinic. Researchers say that methotrexate-vinblastineadriamycin-cisplatin (MVAC) should remain the preferred neoadjuvant chemotherapy for patients with muscleinvasive bladder cancer who have their bladder removed. “The most important message at this time is that for metastatic disease, GC is equivalent to MVAC in terms of tumor response and it has less toxicity, but that doesn’t necessarily translate into patients who don’t have metastatic disease and are candidates for having their bladder removed,” said senior study author Andrew Stephenson, MD, director of the Center for Urologic Oncology at the Glickman Urological and Kidney Institute at Cleveland Clinic. “MVAC is probably the better regimen to use in patients who don’t have metastatic disease and that is something we didn’t know before.” He noted that this was the first study to report on using GC prior to surgery in patients with bladder cancer. Previous studies have shown that patients with muscle-invasive bladder cancers benefit from chemotherapy, whether it is administered before or

after surgery. Because the four-drug regimen MVAC only has been shown to help lead to a complete pathologic response in approximately 30% of patients, headto-head studies have examined whether GC can be an effective alternative and revealed that outcomes are similar with the two regimens, but toxicity is significantly lower with GC. “We tried to move that two-drug combination into the presurgical model to see if we get the same 30% disappearance of tumor using this two-drug regimen. However, the answer was that we did not. That was a surprise to us,” said study investigator Eric Klein, MD, chairman of the Glickman Urological and Kidney Institute and professor of surgery at Cleveland Clinic, Ohio. “What it really showed is that you cannot necessarily translate the use of a combination chemotherapy regimen in one setting and assume it will still have the same effects in another setting.” The investigators, who presented their findings at the 2009 Genitourinary Cancers Symposium, evaluated the outcome of neoadjuvant chemotherapy and open radical cystectomy (RC) in a cohort of patients in a tertiary referral setting. A total of 117 subjects with muscle-invasive

bladder cancer who underwent RC at Cleveland Clinic from January 2006 to November 2007 were studied as part of this retrospective investigation. Of the 117 patients, 29 (25%) received neoadjuvant chemotherapy. Of the 29 patients, 23 (79%) had a clinical stage of T2 and six (21%) had a clinical stage of T3-4a. A total of 20 patients (69%) received GC regimens, four patients (14%) received MVAC and five patients (17%) received other regimens. Among the 29 patients who received neoadjuvant chemotherapy, the median interval from diagnosis of muscle-invasive cancer to RC was 208 days (interquartile range: 149-327 days). Investigators found that in patients who received neoadjuvant chemotherapy, only two patients (7%) achieved a pathologic complete response and 18 patients (62%) were found to have non– organ-confined residual cancer. Overall median progression-free survival was 10.5 months. Dr. Klein said that although the study was small, it might be time to rethink the idea that the two-drug regimen can be used instead of MVAC when delivering chemotherapy prior to surgery. Overall, the study found that few RC

patients experienced a pathologic complete response with neoadjuvant chemotherapy, and the vast majority experienced rapid disease progression. These poor outcomes may be due to the use of non–MVAC-based regimens or excessive delay in performing RC. The investigators concluded that in the absence of supportive data for GC in the neoadjuvant setting, MVAC should remain the preferred regimen. Dr. Klein said it also appeared that excessive delays in performing RC might negate the benefit of neoadjuvant chemotherapy. Martin Gleave, MD, a professor of urologic sciences at the University of British Columbia, Vancouver, Canada, said the findings are clinically significant and that it is important that oncology clinicians are aware of them. He said, however, that it was worth noting that this was a single institution experience reporting on a retrospective study, both of which are notable study limitations. “This study highlights that there may be differences in activity between different chemotherapy regimens,” said Dr. Gleave. “The findings are interesting and it may be that there are significant differences in these different regimens in this setting, but much more research is needed and we have to be careful when looking at a retrospective series.” —John Schieszer

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Neuroblastoma

IMMUNOTHERAPY continued from page 1 �

make this immunotherapy available to more children with neuroblastoma,” Dr. Yu said. She noted that until a company steps in to take over production, the drug is currently only available through the National Cancer Institute (NCI). “This is the first clinical trial to document that a combination of anticancer antibodies with cytokines is an effective anticancer therapy,” said Dr. Yu. “This also is the first time that an antibody targeting a nonprotein antigen, in this case a glycolipid, is shown to be effective for immunotherapy of cancer.” Today, only 30% of patients with high-risk neuroblastoma survive with the conventional treatment, which includes surgery, intensive chemotherapy with stem cell rescue and radiation therapy, followed by RA. In their quest to improve options for patients, investigators tested an antibody-based immunotherapy with chimeric monoclonal anti-GD2-antibody ch14.18. There is a strong rationale for using GD2targeted immunotherapy to treat neuroblastoma.

Immunotherapy Dose Schedule • ch14.18: 25 mg/m2 for 4 days, every 4 weeks • Courses 1, 3, 5: GM-CSF 250 mcg/m2 for 14 days, starting 3 days before ch14.18

relapses occur within the first two years after stem cell transplant, and those neuroblastoma patients who are disease-free for two years after a stem cell transplant will most likely be cured. Overall survival at two years was 86% in patients who received immunotherapy and 75% in patients who received standard treatment (P=0.0223). “This is an extraordinary result of an EFS gain of 20% in the setting of MRD [minimal residual disease] with immunotherapy,” said Ruth Ladenstein, MD, an oncologist at St. Anna Children’s Hospital in Vienna, Austria. “The question is, ‘is the combination a magic bullet and who is the most active partner in this combination?’” Grade 3/4 toxicities were more common in patients receiving immunotherapy, but these were usually controllable and reversible. These included pain (6% vs. 47%), capillary leak (0 vs. 21%), acute allergic reaction (2% vs. 39%) and serum sickness (0 vs. 1%). Capillary leak syndrome and hypersensitivity reaction were more frequent during the IL-2-containing courses. One toxic death resulted from an IL-2 overdose. “There is quite an impact of toxicity in the immunotherapy arm, which is a bit bothersome for the future because we wonder if we can really bring this

‘There is quite an impact of toxicity in the immunotherapy arm, which is a bit bothersome for the future because we wonder if we can really bring this through in a multicenter and multinational setting.’

• Courses 2 and 4: IL-2 4.5 ✕ 106 IU/m2 for 4 days in week 1 IL-2 3.0 ✕ 106 IU/m2 for 4 days in week 2 with ch14.18

More than 99% of neuroblastomas express GD2, and GD2 is not expressed in normal tissues except for tissues of neuroectodermal origin, such as skin, peripheral nerves and brain tissue. GD2 also is expressed by melanoma, glioma, small cell lung cancer, osteocarcinoma and soft tissue sarcoma. The study enrolled children with newly diagnosed, high-risk neuroblastoma who achieved a complete response or partial response to induction therapy and received myeloablative consolidation with stem cell rescue. Half of the children received the standard treatment with 13-cis-RA and the other half received RA plus immunotherapy. Patients were randomized to receive 13-cis-RA for six cycles (standard) or RA for six cycles with five concomitant cycles of ch14.18 combined with granulocytemacrophage colony–stimulating factor (GM-CSF) or interleukin (IL)-2 in alternating cycles. The cytokines, GM-CSF and IL-2, were given to stimulate immune effector cells to enhance antibody-dependent cellular cytotoxicity. Investigators had planned to accrue 386 patients, but in spring 2009, encouraging results with a statistically significant P value (P=0.0115) caused researchers to stop randomizing patients early. The analysis presented at the ASCO annual meeting involved 226 children. After two years, EFS was 66% in patients who received immunotherapy compared with 46% in the standard treatment group (P=0.0115). The 20% improvement in EFS at the two-year mark is especially important since the majority (>90%) of

—Ruth Ladenstein, MD

through in a multicenter and multinational setting,” Dr. Ladenstein said. “But, as the event-free survival and overall survival are indeed very intriguing, very promising and very exciting, I think there is a lot of motivation for parents and doctors to go after this.” She noted that this is not possible for doctors and patients in Europe, because GM-CSF is currently not available on the market there. Currently, the drug is being produced by the NCI and is only available through the Phase III trial. The

trial will continue so that children can have access to the drug and investigators can collect more comprehensive toxicity data sufficient for FDA approval. Dr. Yu said several pharmaceutical companies have expressed interest in taking the drug to market. “We are hoping the biotech industry will take over,” she said. The study was conducted through the Children’s Oncology Group (trial ANBL0032). —Kate O’Rourke

Reid Offringa

• Cis-RA: 160 mg/m2 for 14 days

Above: Rudolf Virchow, the first to describe an abdominal tumor in a child as a “glioma.” Right: MRI showing orbital and skull vault metastatic neuroblastoma in a 2-year-old patient.

Microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Breast

Patients’ Grasp of Breast Cancer Treatment Options Lacking Clinicians may not be adequately informing women of all the facts about their treatment options for early-stage breast cancer, a new study suggests. According to the study, which was presented at the 2008 San Antonio Breast Cancer Symposium (abstract 5098), fewer than one in five women—19%—knew that mastectomy and lumpectomy with radiation offered equivalent survival. The results were based on interviews with more than 240 women who had newly diagnosed stage I or II breast cancer. “Clearly, we have a problem communicating with our patients. If you look at our results, the discussions between surgeons and patients are happening, but we’re not getting our information across,” said Amber A. Guth, MD, senior author of the study and an associate professor of surgery at the New York University School of Medicine, in New York City. “This is an important study that likely does represent the majority of women,” said Lillie Shockney, RN, MAS, University Distinguished Service Assistant Professor of Breast Cancer at Johns Hopkins in Baltimore and chair of the National Consortium of Breast Centers QI Task Force. Dr. Guth and colleagues Nina Bickell, MD, and Shuhbha Dhage, MD, questioned 243 women who underwent a definitive surgical treatment between 2004 and 2006 about their understanding of breast cancer and the communication with their physicians. The women were treated at three municipal hospitals, two tertiary centers and one community hospital in New York City, representing a broad spectrum of care and a wide range of demographic features. All subjects, who were part of a larger study to reduce disparities in breast cancer care, were interviewed an average of 11 months after surgery (range, six to 28 months). Of the women surveyed, 88% said they had discussed a range of surgical treatment options with their doctors. However, only 55% of women said they felt that they had a choice of treatment. Many women believed that lumpectomy with radiation was not an option for them or that breast-conserving surgery would not give them the same chances of survival as mastectomy. Women’s feelings about having a choice were unaffected by race, income, education or cancer stage, the analysis showed. And they were not more likely to undergo either mastectomy or lumpectomy if

they felt they had a choice. Experts who reviewed the study say the survey does not mean that surgeons omit important infor-

‘Women need to hear a full explanation in layman’s terms of what the various surgical options are for the treatment of their breast cancer. Not just what the doctor thinks should be done, but all the options.’ —Lillie Shockney, RN

mation in their talks with patients. Rather, the study reveals a gap between what patients are told in the office and what they understand from their conversations with physicians. “As soon as you mention the word ‘cancer,’ women are stuck on that. They are not absorbing everything that we say. Surgeons need to remember that when they tell women their diagnosis,” said Dr. Guth. Brian O’Hea, MD, a breast cancer surgeon and associate professor of surgery at Stony Brook University School of Medicine, Stony Brook, N.Y., said that his patients are often so upset after learning they have cancer that they don’t really hear everything he says immediately afterward. So he usually calls patients at home in advance of their office visit to give them their diagnosis. “That enables us to have a more productive office visit. It gives her some time to do some research on her own, get past a bit of the initial shock and grief so that in the office visit, she is more likely to be accepting and understanding of the conversations we have,” he said. Dr. O’Hea said the study results were “interesting” but left some questions unanswered. In particular,

it is not clear why the women didn’t feel they had a choice. Some women who have the option of lumpectomy still believe mastectomy is their only real option because it reduces their chances of local recurrence. “Local recurrences are less frequent with mastectomy as compared with lumpectomy, but cancer survival is the same for both choices. “I think it’s important to let a woman know all the options, to give her well-thought-out written explanations that she can take home and … to make a recommendation. Women want our advice, too. They want the benefit of our experience. But the final decision is ultimately theirs.” —Christina Frangou

Liver Cancer

Sorafenib Dosing Poses Problem for Asian Patients San Francisco—In a study of sorafenib administered to patients at the University of California, Irvine, nearly 100% of Asian patients showed poor tolerance of the manufacturer’s recommended initial dose of the drug, researchers reported at the 2009 Gastrointestinal Cancers Symposium (abstract 198). Furthermore, the maximum tolerated dose was significantly lower among Asian than non-Asian patients, according to the investigators.

Sorafenib is the first approved targeted agent for the treatment of hepatocellular carcinoma (HCC), which has a high incidence among Asians, underscoring the importance of finding the optimal dose of this medication for this patient population, said co-investigator David K. Imagawa, MD, chief of hepatobiliary and pancreas surgery at UC Irvine. The first author of the study is Kaylene Barrera, a second-year medical student. “The problem we found, soon after

we started using sorafenib, was that our population, which is largely Asian, had a very difficult time tolerating the drug at the recommended dose,” Dr. Imagawa said. According to the manufacturer, the recommended dose of sorafenib is 400 mg bid, the same dose used in the pivotal Phase III SHARP (Sorafenib HCC Assessment Randomized Protocol) trial. However, that patient population came entirely from Europe, North America

and South America, Dr. Imagawa said (N Engl J Med 2008;359:378-390, PMID: 18650514). To evaluate the use of sorafenib in their predominantly Asian population, the California investigators conducted a retrospective analysis of all patients with HCC treated with sorafenib at UC Irvine Medical Center between February 2007 and June 2008. Drug dosing and toxicities were compared between Asian (n=36) and non-Asian (n=10)

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Gastric Cancer

Asian Americans Live Longer With Gastric Cancer Significant Survival Advantage Likely Due to Tumor Biology Phoenix—Asian Americans, particularly those of Korean descent, who have gastric cancer survive significantly longer than any other ethnic group with this malignancy, according to research presented at the 2009 annual meeting of the Society of Surgical Oncology (SSO). Data from the Los Angeles County Cancer Surveillance Program show that patients of Asian descent who are diagnosed with gastric adenocarcinoma survive nearly twice as long after diagnosis as Hispanic Americans, blacks and whites. The ethnic disparities are not due to differences in surgical technique or access to health care but arise from distinctly different disease types that vary between ethnicities, the study suggests. “We suspect there may be differences in tumor biology among the groups,” explained Brian Mailey, MD, a research fellow in City of Hope’s Division of General Oncologic Surgery, who presented the study. Dr. Mailey and colleagues analyzed more than 13,516 cases of gastric cancer in Los Angeles County, a useful site for study because of its diverse population. Asian Americans comprise 10% of the county’s population but accounted for nearly 25% of the gastric cancer patients studied,

since the disease is more prevalent among those of Asian ancestry due to factors including dietary habits (consumption of smoked, pickled and salted foods). The analysis focused on 7,140 people who underwent surgery with curative intent for their disease. Of these, 38% were white, 10% were black, 25% were Hispanic and 26% were Asian. Asian Americans had dramatically higher survival rates than any other group studied. Typical survival duration was 15.8 months for Asian Americans compared with 8.6 months for Hispanic Americans, 8.1 months for whites and 7.7 months for blacks. About 28% of Asian Americans survived for five years, a marked increase from 16% reported in Latinos, 13.5% in whites and 12% in blacks. Asian Americans were significantly less likely to be diagnosed with distant or regional disease, less likely to have cardia adenocarcinoma and more likely to have surgery compared with the

other ethnic groups (P<0.001). The survival difference between ethnic groups was not related to the diagnostic technique or the site of the cancer. Asians lived longer after diagnosis regardless of whether gastric cancer was discovered in early or late stages, how it was treated and where it was located in the stomach, said senior author Joseph Kim, MD, assistant professor in the Department of Surgery at City of Hope Hospital in Los Angeles. “It’s not really clear why these differences exist, but it’s unlikely to be related to surgical technique,” Dr. Kim said. “We suspect there may be differences in tumor biology among the groups.” The study is the first to show that marked survival gaps exist even between different ethnicities within the Asian American group. With an overall survival of 21.6 months, Korean patients (n=282) had one of the highest survival rates for gastric cancer ever reported. Individuals of Chinese

(n=470) and Vietnamese descent (n=16) survived 16.6 and 16.5 months, respectively, followed by Japanese American patients at 13.5 months. Filipino Americans had the worst outcomes of any Asian American group with an average survival rate of 9.3 months, still higher by about a month than that reported for whites, blacks or Hispanic Americans. “Simply put, this study shows that in L.A. County, Koreans outrank all other ethnic groups in survival from gastric cancer. The important question is why,” said Benjamin Kim, MD, a surgeon of Korean descent and director of the Utah Cancer Institute in Salt Lake City. “The answer, in part, seems to be diagnosis and treatment at an earlier stage [of disease]. We can speculate on possible reasons: diet, such as spicy kim chee, heightened awareness and proactive diagnostic testing due to high incidence of gastric cancer in Koreans. Understanding the underlying factors accounting for improved outcomes may translate into better treatments for all groups.” —Christina Frangou Liver Cancer

patient groups. Disease stage was similar between the groups. Similar to subjects in the SHARP trial, adverse effects—mainly fatigue, handfoot syndrome and diarrhea—were the cause of treatment discontinuation in 35% of patients; however, these occurred at significantly lower doses among Asians, according to Dr. Imagawa. In the Asian group, only one patient tolerated the FDA-indicated dose of 400 mg bid. “This was a young patient who was 6 ft 2 in [tall] and weighed 280 pounds,” Dr. Imagawa said. “We are dosing this drug based on a onesize-fits-all approach, but our Asian population tends to be diminutive and petite,” he said. “We know that the body surface area of Asians is significantly lower than for non-Asians with HCC, and we think that the pharmacokinetics may even be different between the groups. This needs further study.”

Full Doses Not Tolerated By Most Sorafenib at a dose of 200 mg bid— half the recommended dose—was tolerated by 70% of the Asian patients in the study, while 14% tolerated only 200 mg per day and 14% did not tolerate sorafenib at all. Among the non-Asian patients, 40% tolerated the full 400-mg

Table. Maximum Tolerated Dose of Sorafenib in HCC Patients

Maximum Tolerated Dose

Asian Patients, n (%)a

Non-Asian Patients, n (%)b

0 mg (no dose tolerated)

5 (14)

200 mg per day

5 (14)

200 mg bid

25 (70)

5 (50)

400 mg/200 mg per day

1 (10)

400 mg bid

1 (3)

4 (40)

Did not tolerate 400 mg bid

35 (97)

6 (60)

n=36; b n=10; HCC, hepatocellular carcinoma

bid dose, while 50% tolerated 200 mg bid and 10% (one patient) tolerated a dose of 400 mg/200 mg per day (Table). Thus, the recommended dose of 400 mg bid was not tolerated by 97% of Asians compared with 60% of non-Asians (P<0.01). Early discontinuation of sorafenib occurred for 39% and 20% of patients, respectively. At the time of the study, 39% of Asians with HCC were still taking sorafenib compared with 50% of non-Asians. Dr. Imagawa said that for their Asian patients, his team now initiates treatment at 200 mg once daily, escalates to 200 mg bid, and then to 400 mg bid in

the rare patient who can tolerate the dosage. Whether the reduced dosage will compromise efficacy in HCC is unknown, he said. He added that even in “standard” patient populations, sorafenib is a drug that is very difficult to tolerate, since across the board approximately 30% discontinue use and about 40% require dose reductions. “On the other hand, one way we know the drugs are working is by their side-effect profile,” he said. Commenting on the findings, Pius Maliakal, PhD, clinical specialist in oncology research at M.D. Anderson Cancer Center Orlando, in Florida,

suggested that genetic polymorphisms in human cytochrome P450 (CYP) isozymes may play a role in Asians’ poor tolerance of sorafenib. “Although sorafenib is a good substrate for the CYP3A4 isozyme, other CYP isozymes that are very prone to genetic polymorphisms may also be involved in its metabolism,” he said. “Furthermore, the dietary habits of the Asian population versus Caucasians may also play a role because the bioavailability of oral sorafenib is only 40% to 50%, and its absorption is greatly reduced by fatty meal co-ingestion,” Dr. Maliakal said. “I think further studies are warranted to compare the plasma levels of sorafenib in these two populations after fixed doses.” Ed Chu, MD, chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn., said the study highlights an important clinical point but more research is needed to determine whether the reduced dosing in Asian patients may compromise clinical efficacy. “My concern is that while the dose reduction will improve the side effect profile, it could significantly reduce clinical efficacy,” Dr. Chu said. —Caroline Helwick

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CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

New Phase II and III Clinical Trials Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to July 7, 2009. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Solid Tumors

Protocol Type

Age

Protocol ID

Trial Sites

Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi’s Sarcoma, Phase II

18 and over

090130

Cisplatin or Carboplatin and Sorafenib in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery, Phase II

18 and over

CDR0000639032

Randomized Study of Adjuvant Therapy Comprising Tamoxifen Citrate Alone Versus Ovarian Function Suppression and Tamoxifen Citrate Versus Ovarian Function Suppression and Exemestane in Premenopausal Women With Hormone Receptor-Positive Breast Cancer, Phase III

Premenopausal

ICORG-06-02

Anti-Hormone Therapy With Anastrozole and Fulvestrant Before Surgery to Treat Postmenopausal Women With Breast Cancer, Phase II

Over 18

11595

Randomized Study of Neoadjuvant Cisplatin and Paclitaxel With or Without Everolimus in Patients With Triple-Negative, Stage II or III Breast Cancer, Phase II

Not specified

VU-VICC-BRE-0904

Statins and Breast Cancer Biomarkers, Phase II

35 to 55

V0407

CA, DE, MA, NC, NV, VT

A Study of Stimuvax in Combination With Hormonal Treatment Versus Hormonal Treatment Alone for First-Line Therapy of Endocrine-Sensitive Advanced Breast Cancer, Phase III

Postmenopausal

EMR 200038-010

Randomized Pilot Study of HER2/neu Peptide-Pulsed Autologous Type 1 Dendritic Cell Vaccine in Patients With Ductal Carcinoma In Situ of the Breast, Phase II

Over 18

UPCC-15107

Xeloda (Capecitabine) and External Beam Radiation in Breast Cancer, Phase II

Over 18

2009-0087

Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer, Phase II

18 and over

ALSSMBC0804

MT, TN

Trastuzumab With or Without Everolimus in Estrogen Receptor-Positive Metastatic Breast Cancer, Phase II

Over 18

WCI1524-0

Surgery and Oxaliplatin or Mitomycin C in Treating Patients With Primary Colorectal Tumors or Tumors of the Appendix

18 and over

NCI-2009-00947

Vorinostat, Carboplatin and Gemcitabine Plus Vorinostat Maintenance in Women With Recurrent, Platinum-Sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer, Phase II

18 and over

09-026

Targeted Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary, Phase I/II

18 to 80

090089

XAD - Xelox (Capecitabine + Oxaliplatin) + Bevacizumab + Dasatinib for Solid Tumors, Phase II

18 and over

10354

A Broad Multi-Histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) In Advanced Colorectal, Non-Small Cell Lung, Head and Neck, Hepatocellular and Renal Cell Carcinomas and Pheochromocytoma and Thyroid Tumors, Phase II

18 and over

090138

A Study of MM-111 in Patients With Advanced Her2 Positive Cancers, Phase II

18 to 80

MM-111

Effect of Talactoferrin in Adults With Non-Small Cell Lung Cancer, Phase II

18 to 90

080166

Pioglitazone to Treat Adults Undergoing Surgery for Non-Small Cell Lung Cancer, Phase II

18 and over

090076

MD, NY

Vaccine Therapy in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer Who Have Finished First-Line Chemotherapy, Phase II

18 and over

EPROST-20057158

Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer, Phase II

18 and over

080078

Therapy to Treat Ewing’s Sarcoma, Rhabdomyosarcoma or Neuroblastoma, Phase II

19 months to 35 years

070206

Study of Metastatic Renal Cancer Using T-Cells Transduced With a T-Cell Receptor Which Recognizes TRAIL Bound to the DR4 Receptor, Phase II

18 and over

090092

Bevacizumab, Autologous Tumor/DC Vaccine, IL-2 and IFNa-2b in Metastatic Renal Cell Carcinoma (RCC) Patients, Phase II

18 and over

D0708

Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status, Phase II

18 and over

D9010C00008

CA, CO, WA

Sorafenib for Patients With Metastatic or Recurrent Esophageal and Gastroesophageal Junction Cancer, Phase II

18 and over

09-016

Chemotherapy Followed by Infusion of DMF5 Cells to Treat Metastatic Melanoma, Phase II

18 and over

070210

Pegylated Arginine Deiminase in Treating Patients With Metastatic Melanoma That Cannot Be Removed by Surgery, Phase II

Over 18

CDR0000537488

Study of Gene Modified Immune Cells in Patients With Advanced Melanoma, Phase II

18 and over

08-02-020

Safety Study of Sorafenib With Androgen Deprivation and Radiotherapy to Treat Prostate Cancer, Phase II

Over 18

IRB# 004-08

Single Agent Temsirolimus (Torisel) in Chemotherapy-naïve Castration-Resistant Prostate Cancer Patients, Phase II

18 and over

OSRI 0901

Azacitidine, Docetaxel, and Prednisone in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy, Phase II

18 and over

CDR0000558043

FACBC PET/CT Used in the Diagnosis of Primary Prostate Cancer, Phase II

18 and over

FACBC

Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer, Phase II

Over 18

Pro00012159

Treatment of Advanced Head and Neck Cancer With Opioid Growth Factor, Phase II

Over 18

23429

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CLINICAL TRIALS

Supportive

Hematologic Malignancies

Solid Tumors

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • JULY 2009

Protocol Type

Age

Protocol ID

Trial Sites

International Study: Comparison of Two Treatments for Adrenocortical Cancer, Phase III

18 to 80

080176

Effect of NovoTTF-100A Together With Temozolomide in Newly Diagnosed Glioblastoma Multiforme, Phase III

18 and over

EF-14

ME, NJ, TX

Reproducibility of 18F Uptake by Solid Tumors Using PET Imaging Following Intravenous Administration of (18F) Injection, Phase II

18 and over

GE-135-004

Clinical Trial of Ixabepilone (Ixempra, BMS-247550, NSC 710428), an Epothilone B Analog, in Cervical Cancer, Phase II

18 to 80

090037

Sunitinib Malate in Refractory Germ Cell Tumors, Phase II

18 and over

2006-0685

Retreatment Protocol for BL22 Immunotherapy in Relapsed or Refractory Hairy Cell Leukemia, Phase II

18 and over

090076

Rituximab and Combination Chemotherapy in Treating Patients With Previously Untreated Mantle Cell Lymphoma, Phase II

18 to 64

CDR0000639057

Stem Cell Transplant for Hematological Malignancy, Phase III

54 and under

0107M05202

Study of Induction Therapy Comprising Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab Followed by Maintenance Therapy Comprising Vorinostat and Rituximab in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, Phase II

18 and over

PSOC-2401

Wilm’s Tumor1 Protein Vaccine to Treat Cancers of the Blood, Phase II

1 to 74

080051

Study of Metastatic Cancer That Expresses Carcinoembryonic Antigen Using Lymphodepleting Conditioning Followed by Infusion of Anti-CEA TCR-Gene Engineered Lymphocytes, Phase II

18 and over

090047

Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer, Phase II

18 to 75

080088

MD, NJ

Study of Carfilzomib in Relapsed Multiple Myeloma, Phase II

18 and over

PX-171-004

AZ, CA, FL, GA, IL, KY, MI, MN, MS, NJ, NY, OH, TX

Study of Bendamustine Combined With Bortezomib for Patients With Relapsed/Refractory Multiple Myeloma, Phase II

18 and over

C18083/1063/ MM/US

CA, MD, SC, TN

A Study of Noscapine HCl (CB3304 ) in Patients With Relapsed or Refractory Multiple Myeloma, Phase II

18 and over

COU-NOS-001

CA, NY

Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma, Phase II

18 and over

NCI-2009-00934

Genes in Predicting Outcome of Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab and Combination Chemotherapy, Phase II

Over 18

CDR0000537678

Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia, Phase II

18 and over

090025

Yttrium Y 90 Ibritumomab Tiuxetan and Rituximab in Treating Patients With Previously Untreated Marginal Zone Lymphoma, Phase II

18 and over

CDR0000537500

Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer That Did Not Respond to First-Line Therapy With Gemcitabine, Phase II

18 and over

CDR0000597455

Study of Arginine Butyrate and Ganciclovir/Valganciclovir in EBV(+) Lymphoid Malignancies, Phase II

3 and over

P2 L-D AB

Fondaparinux in Preventing Blood Clots in Patients Undergoing Surgery for Gynecologic Cancer, Phase II

18 and over

CDR0000503985

MN, PA

A Study to Evaluate the Safety and Efficacy of Dasatinib (Sprycel) in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Phase II

Over 18

0809009979

Randomized Study of Low-Dose Versus Standard-Dose Glucocorticoids as Initial Treatment for Patients With Newly Diagnosed Acute Graft-Versus-Host Disease, Phase III

Not specified

FHCRC-2327.00

Selective Publication of Drug Data Suggests Bias A study has found inconsistencies between drug trial information that is reviewed by the FDA and that which is published and available to clinicians. The new findings uncover a potential information bias, because positive trial results reviewed by the FDA were far more likely to be published in peerreviewed journals than negative ones. Previous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The new study set out to determine the publication rate of efficacy trials submitted

to the FDA in approved new drug applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications. The observational study included all efficacy trials found in approved NDAs for new molecular entities from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. Of the 164 FDA-reviewed NDA

efficacy trials included in this study, 78% (128) were published in medical journals. Primary outcomes from the reviews were completely omitted in 25% (41) of the published findings. Furthermore, of the 43 NDA reviews that resulted in unfavorable outcomes, 47% (20) were excluded from published findings. The researchers also found that published information was altered to augment a drug’s supposed efficacy. Of the 23 NDA reviews with unfavorable outcomes that were eventually published, four outcomes were changed between the FDA review of the trial and

publication to favor the drug (P=0.38). A total of 99 conclusions were provided in both the NDAs and the research papers, and nine conclusions were changed after FDA review to favor the tested drug. Fifteen primary outcomes that favored the drug were published in journals but were not recorded in the NDAs. The investigators also noted that FDA-reviewed trial data, including those reported in NDAs, often go unpublished for several years. These findings appeared in PLoS Medicine (2008;5:e217, PMID: 19067477). —Seth Kandel

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